A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders.

Altered synaptic structure and function is a major hallmark of fragile X syndrome (FXS), autism spectrum disorders (ASDs), and other intellectual disabilities (IDs), which are therefore classified as synaptopathies. FXS and ASDs, while clinically and genetically distinct, share significant comorbidity, suggesting that there may be a common molecular and/or cellular basis, presumably at the synapse. In this article, we review brain architecture and synaptic pathways that are dysregulated in FXS and ASDs, including spine architecture, signaling in synaptic plasticity, local protein synthesis, (m)RNA modifications, and degradation. mRNA repression is a powerful mechanism for the regulation of synaptic structure and efficacy. We infer that there is no single pathway that explains most of the etiology and discuss new findings and the implications for future work directed at improving our understanding of the pathogenesis of FXS and related ASDs and the design of therapeutic strategies to ameliorate these disorders

Gradient-enriched finite element methodology for axisymmetric problems

Due to the axisymmetric nature of many engineering problems, bi-dimensional axisymmetric finite elements play an important role in the numerical analysis of structures, as well as advanced technology micro/nano-components and devices (nano-tubes, nano-wires, micro-/nano-pillars, micro-electrodes). In this paper, a straightforward (Formula presented.)-continuous gradient-enriched finite element methodology is proposed for the solution of axisymmetric geometries, including both axisymmetric and non-axisymmetric loads. Considerations about the best integration rules and an exhaustive convergence study are also provided along with guidances on optimal element size. Moreover, by applying the present methodology to cylindrical bars characterised by a circumferential sharp crack, the ability of the present methodology to remove singularities from the stress field has been shown under axial, bending, and torsional loading conditions. Some preliminary results, obtained by applying the proposed methodology to notched cylindrical bars, are also presented, highlighting the accuracy of the methodology in the static and fatigue assessment of notched components, for both brittle and ductile materials. Finally, the proposed methodology has been applied to model the unit cell of the anode of Li-ion batteries showing the ability of the methodology to account for size effects

Gradient elasticity: a new tool for the multiaxial high-cycle fatigue assessment of notched components

In this paper, the accuracy of gradient elasticity in estimating the fatigue strength of engineering components, characterised by the presence of stress risers and subjected to multiaxial high-cycle fatigue loadings, is assessed. In particular, a new approach, based on the combination of the Ru-Aifantis theory of gradient elasticity and the Theory of Critical Distances (TCD), is proposed for the fatigue assessment of notched metallic components. The proposed methodology represents an important step forward respect to the state of the art, allowing an accurate fatigue assessment of engineering components, by post-processing the relevant gradient-enriched stresses directly on the surface of the component, with evident advantages from a practical point of view

Molecular dynamics simulations show how the FMRP Ile304Asn mutation destabilizes the KH2 domain structure and affects its function

Mutations or deletions of FMRP, involved in the regulation of mRNA metabolism in brain, lead to the Fragile X syndrome (FXS), the most frequent form of inherited intellectual disability. A severe manifestation of the disease has been associated with the Ile304Asn mutation, located on the KH2 domain of the protein. Several hypotheses have been proposed to explain the possible molecular mechanism responsible for the drastic effect of this mutation in humans. Here, we performed a molecular dynamics simulation and show that the Ile304Asn mutation destabilizes the hydrophobic core producing a partial unfolding of two α-helices and a displacement of a third one. The affected regions show increased residue flexibility and motion. Molecular docking analysis revealed strongly reduced binding to a model single-stranded nucleic acid in agreement with known data that the two partially unfolded helices form the RNA-binding surface. The third helix, which we show here to be also affected, is involved in the PAK1 protein interaction. These two functional binding sites on the KH2 domain do not overlap spatially, and therefore, they can simultaneously bind their targets. Since the Ile304Asn mutation affects both binding sites, this may justify the severe clinical manifestation observed in the patient in which both mRNA metabolism activity and cytoskeleton remodeling would be affected

WebGIS as boundary tools between scientific geoinformation and disaster risk reduction action in volcanic areas

As the amount of spatial data is growing, there is increased interest in developing tools to explore, visualize and interpret them, with the final aim of informing decision making efficiently. Within the European MIAVITA project, we examined this issue in the case of volcanic areas, where existing geospatial databases are particularly complex due to the number of threats to be considered, including volcanic (e.g. lava flows, ash fall) and non-volcanic hazards, such as landslides or tsunamis. We involved a group of hazard and risk analysts and managers, civil security officers, GIS analysts and system developers to design a Web-based geographical information system (WebGIS). We tested the system at the Mount Cameroon volcano, taking advantage of a complex hazard and risk geographical database. This study enabled identifying key requirements for such tools in volcanic areas, such as the need to manage user privileges differently according to their profile and the status of the volcano. This work also highlights that, in addition to the development of large geoinformation clearinghouses, there is a need for site-specific information systems focused on working procedures of users, in order to fill the last gap between data producers and users

Gradient-enriched linear-elastic tip stresses to perform the high-cycle fatigue assessment of notched plain concrete

Gradient Elasticity (GE) allows the stress analysis to be performed by taking into account the size of the dominant source of microstructural heterogeneity via a suitable length scale parameter. This is done by simply assuming that the material under investigation obeys a linear-elastic constitutive law, albeit equipped with additional spatial strain gradients. From a practical point of view, the most important implication of this modus operandi is that gradient-enriched linear-elastic stresses at the notch tips are always finite, this holding true also in the presence of sharp stress risers (such as cracks). In the present investigation, the accuracy of two different GE based design strategies was checked against a number of experimental results generated by testing, under cyclic four-point bending, plain concrete samples containing different geometrical features. The high level of accuracy which was obtained by directly using gradient-enriched linear-elastic notch stresses strongly supports the idea that GE is a powerful tool suitable for designing notched concrete components against high-cycle fatigue. This result is very promising also because the required stress analysis can directly be performed by using standard Finite Element (FE) solvers

Clinical and Molecular Assessment in a Female with Fragile X Syndrome and Tuberous Sclerosis.

Fragile X syndrome (FXS) and tuberous sclerosis (TSC) are genetic disorders that result in intellectual disability and an increased prevalence of autism spectrum disorders (ASD). While the clinical presentation of each disorder is distinct, the molecular causes are linked to a disruption in the mTORC1 (mammalian Target of Rapamycin Complex 1) and ERK1/2 (Extracellular signal-Regulated Kinase) signaling pathways. We assessed the clinical and molecular characteristics of an individual seen at the UC Davis MIND Institute with a diagnosis of FXS and TSC. Clinical evaluation of physical, behavioral, and cognitive impairments were performed. Additionally, total and phosphorylated proteins along the mTORC1 and ERK1/2 pathways were measured in primary fibroblast cell lines from the proband. In this case the phenotypic effects that result in a human with both FXS and TSC are shown to be severe. Changes in mTORC1 and ERK1/2 signaling proteins and global protein synthesis were not found to be noticeably different between four cohorts (typically developing, FMR1 full mutation, FMR1 full mutation and TSC1 loss of function mutation, and TSC1 loss of function mutation); however cohort sizes prevented stringent comparisons. It has previously been suggested that disruption of the mTORC1 pathway was reciprocal in TSC and FXS double knock-out mouse models so that the regulation of these pathways were more similar to wild-type mice compared to mice harboring a Fmr1(-/y) or Tsc2(-/+) mutation alone. However, in this first reported case of a human with a diagnosis of both FXS and TSC, substantial clinical impairments, as a result of these two disorders were observed. Differences in the mTORC and ERK1/2 pathways were not clearly established when compared between individuals with either disorder, or both

Absence of RNA-binding protein FXR2P prevents prolonged phase of kainate-induced seizures.

Status epilepticus (SE) is a condition in which seizures are not self-terminating and thereby pose a serious threat to the patient's life. The molecular mechanisms underlying SE are likely heterogeneous and not well understood. Here, we reveal a role for the RNA-binding protein Fragile X-Related Protein 2 (FXR2P) in SE. Fxr2 KO mice display reduced sensitivity specifically to kainic acid-induced SE. Immunoprecipitation of FXR2P coupled to next-generation sequencing of associated mRNAs shows that FXR2P targets are enriched in genes that encode glutamatergic post-synaptic components. Of note, the FXR2P target transcriptome has a significant overlap with epilepsy and SE risk genes. In addition, Fxr2 KO mice fail to show sustained ERK1/2 phosphorylation induced by KA and present reduced burst activity in the hippocampus. Taken together, our findings show that the absence of FXR2P decreases the expression of glutamatergic proteins, and this decrease might prevent self-sustained seizures